SUMMARY The goal of our Collaboratory is to develop novel combined immunologic approaches to cure HIV-1 through a highly collaborative and multifaceted research program involving leading investigators in academia, government, and industry. Our overall hypothesis is that a combined immunologic approach that optimizes antiviral humoral and cellular immune responses, together with latency reversal and possibly lymphoid sanctuary disruption, will effectively reduce or control the viral reservoir in ART- suppressed, SHIV-infected rhesus monkeys and in ART-suppressed, HIV-1-infected humans to achieve a functional cure. We propose two interactive Research Foci and five Scientific Research Support Sections (Clinical, Nonhuman Primate, Virology, Immunology, and Biostatistics and Bioinformatics). Focus 1: Efficacy of Combined Immunologic Approaches to Target the Viral Reservoir In this Focus, we will evaluate the efficacy of best-in-class broadly neutralizing monoclonal antibodies (bnMAbs), therapeutic vaccines, and latency reversing agents (LRAs) in both SHIV-infected rhesus monkeys and HIV-1-infected humans. These studies will fill a critical knowledge gap by defining the capacity of leading immunologic interventions to target viral reservoirs and to contribute to an HIV-1 cure. Specific Aim 1. To evaluate two leading therapeutic vaccines in ART-suppressed, HIV-1-infected humans treated during acute HIV-1 infection; Specific Aim 2. To evaluate the combination of bnMAbs and a therapeutic vaccine in ART-suppressed, SHIV- infected rhesus monkeys; and Specific Aim 3. To evaluate the combination of optimal bnMAbs and a therapeutic vaccine in ART- suppressed, HIV-1-infected humans treated during both acute and chronic HIV-1 infection. Focus 2: Mechanisms and Next Generation Strategies to Target the Viral Reservoir A major knowledge gap is that we currently do not know which anatomic viral sanctuary gives rise to viral rebound following discontinuation of ART. In this Focus, we will evaluate the impact of bnMAbs, therapeutic vaccines, and LRAs on the viral reservoir, and we will define the anatomic location of the residual viral reservoir that persists despite these interventions with the goal of developing next generation HIV-1 cure strategies. Specific Aim 1. To define the mechanism of action of leading bnMAbs, therapeutic vaccines, and LRAs in depleting the viral reservoir in ART-suppressed, SHIV-infected rhesus monkeys; Specific Aim 2. To develop more effective bnMAbs for reservoir depletion; and Specific Aim 3. To test an improved HIV-1 cure strategy in ART-suppressed, SHIV-infected rhesus monkeys.